There are 10 million people with osteoporosis in the U.S., and approximately one-half have been treated with bisphosphonates. Bisphosphonates suppress bone resorption, and are effective in increasing/maintaining bone mineral density and reducing fracture incidence. Recently, long-term bisphosphonate use has been linked to a newly recognized type of bone fracture called an atypical femoral fracture (AFF). Evidence suggests that AFFs are stress fractures that develop over time and do not heal. But the underlying causes and patient factors contributing to AFFs are not known. In general, stress fractures develop when bone microdamage propagates and coalesces faster than it can be repaired by osteoclast-initiated remodeling. Bisphosphonates may increase the risk of AFF by inhibiting bone resorption and the coupled remodeling that should repair bone microdamage. However, there is no direct evidence that suppression of damage-driven remodeling contributes to AFFs. One reason why the cause of AFFs is unknown is the lack of a suitable animal model to study the pathophysiology. In fact, the 2010 task force of the American Society of Bone and Mineral Research stated that animal models that more accurately mimic atypical fractures need to be developed. The goal of this R21 project is to develop a novel stress fracture model with the key features of an atypical femur fracture. These features include: stress fracture developing on the tensile side, and presence of microdamage-driven bone remodeling prior to stress fracture. Current stress fracture models lack these clinically relevant features. With the new model we will begin to test the general hypothesis that bisphosphonates increase the risk of a non-healing stress fracture by interfering with targeted remodeling of bone microdamage. Development of a clinically relevant stress fracture model will provide a new tool to elucidate the pathogenesis of AFFs including the role of bisphosphonates. Development of a novel model that fits an unmet need in translational bone biology is appropriate to the R21 funding mechanism.